Fused [7,5] bicyclic pyrazole derivatives and methods of use thereof for the treatment of herpesviruses

Abstract

The present invention relates to novel Fused [7,5] Bicyclic Pyrazole Derivatives of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein X, R1, R2, R3, and R4 are as defined herein. The present invention also relates to compositions comprising at least one Fused [7,5] Bicyclic Pyrazole Derivative, and methods of using the Fused [7,5] Bicyclic Pyrazole Derivatives for treating or preventing a herpesvirus infection in a patient.

What is claimed is: 
     
         1 . A compound having of the formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 X is N or C(R 5 ); 
 R 1  is —(C 1 -C 6  alkylene)-(4 to 7-membered monocyclic heterocycloalkyl), or —(C 1 -C 6  alkylene)-(5 or 6-membered monocyclic heteroaryl), wherein said 4 to 7-membered monocyclic heterocycloalkyl group, and said 5 or 6-membered monocyclic heteroaryl group, can each be optionally substituted with one or more RA groups, which can be the same or different; 
 R 2  is selected from C 1 -C 6  alkyl, C 3 -C 6  monocyclic cycloalkyl, —(C 1 -C 6  alkylene)-N(R 6 ) 2 , C 1 -C 6  haloalkyl, and C 1 -C 6  hydroxyalkyl, wherein said C 3 -C 6  monocyclic cycloalkyl group can be optionally substituted with one or more R B  groups, which can be the same or different; 
 R 3  is H or C 1 -C 6  alkyl; 
 R 4  is phenyl, which can be optionally substituted with one or more groups, which can be the same or different, and are selected from: halo, CN, and NO 2 ; 
 R 5  is selected from H, C 1 -C 6  alkyl and —OH; 
 each occurrence of R 6  is independently selected from H, C 1 -C 6  alkyl, and —C(O)R 7 ; 
 each occurrence of R 7  is independently selected from H, C 1 -C 6  alkyl, and C 3 -C 6  monocyclic cycloalkyl, wherein C 3 -C 6  monocyclic cycloalkyl can be optionally substituted with a group selected from C 1 -C 6  alkyl, halo, and —OH; 
 each occurrence of R A  is independently selected from oxo, halo, and C 1 -C 6  alkyl; and 
 each occurrence of R B  is independently selected from C 1 -C 6  alkyl, —OH, —O—(C 1 -C 6  alkyl), halo, —C 1 -C 6  haloalkyl, phenyl, and —C 1 -C 6  hydroxyalkyl. 
 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from H, methyl, ethyl, isopropyl, —CHF 2 , —CH 2 CH(OH)CH(CH 3 ) 2 , —CH 2 C(OH)(CH 3 ) 2 , —CH 2 CH 2 NHC(O)CH(CH 3 ) 2 , —CH 2 CH 2 NHC(O)-cyclobutanyl, —CH 2 CH 2 N(CH 3 )C(O)-cyclobutanyl, and —CH 2 CH 2 N(CH 3 )C(O)-cyclopropanyl, wherein said cyclopentanyl group, said cyclobutanyl group, and said cyclopropanyl group can be optionally substituted with one or more of the following groups, which can be the same or different: F, Cl, methyl, ethyl, isopropyl, isobutyl, t-butyl, methoxy, ethoxy, —OH, —CH 2 OH, —CH 2 F, and phenyl. 
     
     
         6 . The compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2  is methyl. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is H. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is phenyl substituted with one or more of the following groups, which can be the same or different: F, Cl and CN. 
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4  is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is H. 
     
     
         11 . A compound selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . A pharmaceutical composition comprising an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition of  claim 12  further comprising one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents, and immunomodulators. 
     
     
         14 . A method of treating a patient infected with a herpesvirus, comprising the step of administering an amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, effective to treat infection by said herpesvirus in said patient. 
     
     
         15 . The method of  claim 14 , further comprising administering one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents, and immunomodulators. 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein said additional therapeutic agents comprise letermovir. 
     
     
         17 . The method of  claim 15 , wherein said additional therapeutic agents comprise letermovir.